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FROM THE ACADEMY

Guidelines of care for the management of atopic dermatitis

Section 1. Diagnosis and assessment of atopic dermatitis

Work Group: Co-chair, Lawrence F. Eichenfield, MD,a Wynnis L. Tom, MD,a Sarah L. Chamlin, MD, MSCI,b

Steven R. Feldman, MD, PhD,c Jon M. Hanifin, MD,d Eric L. Simpson, MD,d Timothy G. Berger, MD,e

James N. Bergman, MD,f David E. Cohen, MD,g Kevin D. Cooper, MD,h Kelly M. Cordoro, MD,e

Dawn M. Davis, MD,i Alfons Krol, MD,d David J. Margolis, MD, PhD, j Amy S. Paller, MS, MD,k

Kathryn Schwarzenberger, MD,l Robert A. Silverman, MD,m Hywel C. Williams, PhD,n Craig A. Elmets, MD,o

Julie Block, BA,p Christopher G. Harrod, MS,q Wendy Smith Begolka, MBS,q and

Co-chair, Robert Sidbury, MDr

San Diego, San Francisco, and San Rafael, California; Chicago and Schaumburg, Illinois; Winston-Salem,

North Carolina; Portland, Oregon; Vancouver, British Columbia, Canada; New York, New York;

Cleveland, Ohio; Rochester, Minnesota; Philadelphia, Pennsylvania; Burlington, Vermont; Fairfax,

Virginia; Nottingham, United Kingdom; Birmingham, Alabama; and Seattle, Washington

Atopic dermatitis (AD) is a chronic, pruritic, inflammatory dermatosis that affects up to 25% of childrenand 2% to 3% of adults. This guideline addresses important clinical questions that arise in themanagement and care of AD, providing updated and expanded recommendations based on the availableevidence. In this first of 4 sections, methods for the diagnosis and monitoring of disease, outcomesmeasures for assessment, and common clinical associations that affect patients with AD arediscussed. Known risk factors for the development of disease are also reviewed. ( J Am Acad Dermatol2014;70:338-51.)

Key words: assessment scales; atopic dermatitis; biomarkers; clinical associations; criteria; diagnosis;risk factors.

DISCLAIMER Adherence to these guidelines will not ensure

successful treatment in every situation. In addition,these guidelines should not be interpreted assetting a standard of care, or be deemed inclusiveof all proper methods of care nor exclusive of other methods of care reasonably directed toobtaining the same results. The ultimate judgment

regarding the propriety of any specific therapy must be made by the physician and the patient inlight of all the circumstances presented by theindividual patient and the known variability andbiologic behavior of the disease. This guidelinereflects the best available data at the time theguideline was prepared. The results of future

From the Division of Pediatric and Adolescent Dermatology,a Rady

Children’s Hospital San Diego; Department of Dermatology,b

Ann and Robert H. Lurie Children’s Hospital of Chicago;Department of Dermatology,c Wake Forest University Health

Sciences, Winston-Salem; Department of Dermatology,d Ore-

gon Health and Science University; Department of Dermatolo-

gy,e University of California San Francisco; Department of

Dermatology and Skin Science,f University of British Columbia;

Ronald O. Perelman Department of Dermatology,g New York

University School of Medicine; Department of Dermatology,h

Case Western University, Cleveland; Department of Dermato-

logy,i Mayo Clinic, Rochester; Department of Biostatistics and

Epidemiology, j University of Pennsylvania School of Medicine;

Department of Dermatology,k Northwestern University Fein-

berg School of Medicine; Division of Dermatology,l Fletcher

Allen Health Care, Burlington; private practice,m Fairfax; Centre

of Evidence-Based Dermatology,

n

Nottingham University

Hospitals NHS Trust, Nottingham; Department of Dermatolo-

gy,o University of Alabama at Birmingham; National Eczema

Association,p San Rafael; American Academy of Dermatology,q

Schaumburg; and the Department of Dermatology,r Seattle

Children’s Hospital.

Funding sources: None.

The authors’ conflicts of interest/disclosure statements appear at

the end of the article.

Accepted for publication October 5, 2013.

Reprint requests: Wendy Smith Begolka, MBS, American Academy

of Dermatology, 930 E Woodfield Rd, Schaumburg, IL 60173.

E-mail: [email protected].

Published online December 2, 2013.

0190-9622/$36.00

2013 by the American Academy of Dermatology, Inc.

http://dx.doi.org/10.1016/j.jaad.2013.10.010

338

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Abbreviations used:

AAD: American Academy of Dermatology AD: atopic dermatitis ADHD: attention deficit hyperactivity disorderCDLQI: Children’s Dermatology Life Quality IndexDFI: Dermatitis Family ImpactDLQI: Dermatology Life Quality IndexEASI: Eczema Area and Severity IndexFLG: filaggrinGREAT: Global Resource for Eczema TrialsIGA: Investigator’s Global AssessmentIgE: immunoglobulin EIL: interleukinISAAC: International Study of Asthma and Allergies

in ChildhoodMDC: macrophage-derived chemoattractantPOEM: Patient-Oriented Eczema MeasureSASSAD: Six Area, Six Sign Atopic DermatitisSCORAD:SCORing Atopic DermatitisSORT: strength of recommendation taxonomy TARC: thymus and activation-regulated chemokineTISS: Three-Item Severity Scale

UK: United Kingdom

studies may require revisions to the recommenda-tions in this guideline to reflect new data.

SCOPEThis guideline addresses the diagnosis and

assessment of pediatric and adult atopic dermatitis(AD; atopic eczema) of all severities. Other forms of dermatitis, such as irritant dermatitis and allergiccontact dermatitis in those without AD, are outside

of the scope of this document. Recommendations on AD treatment and management are subdivided into 4sections given the significant breadth of the topic andto update and expand on the clinical information andrecommendations previously published in 2004. Thisdocument is the first section in the series and coversmethods for diagnosis and monitoring of AD, diseaseseverity and quality of life scales for outcomes mea-surement, and common clinical associations thataffect patients. A discussion on known risk factorsfor the development of AD is also presented. Thesecond guideline in the series will address the man-

agement and treatment of AD with pharmacologicand nonpharmacologic topical modalities; the thirdsection will cover phototherapy and systemic treat-ment options; and the fourth section will address theminimization of disease flares, educational interven-tions, and use of adjunctive approaches.

METHOD A work group of recognized AD experts was

convened to determine the audience and scope of the guideline, and to identify important clinicalquestions in the diagnosis and assessment of AD(Table I). Work group members completed a

disclosure of interests that was updated and reviewed for potential relevant conflicts of interestthroughout guideline development. If a potentialconflict was noted, the work group member recusedhim or herself from discussion and drafting of recommendations pertinent to the topic area of thedisclosed interest.

An evidence-based model was used and evidence was obtained using a systematicsearchof PubMed,theCochraneLibrar y , andthe Global Resource forEczemaTrials (GREAT)1 databases from November 2003through November 2012 for clinical questions ad-dressed in the previous version of this guidelinepublished in 2004, and from 1964 to 2012 for all newly identifiedclinical questions as determinedby the workgroup to be of importance to clinical care. Searches were prospectively limited to publications in theEnglish language. MeSH terms used in various

combinations in the literature search included: atopicdermatitis, atopic eczema, diagnosis, diagnostic,severity course, assessment, biomarkers, outcomesmeasures, morbidity, quality of life, appearance, co-morbidity, food allergy, allergic rhinitis, asthma, can-cer, sleep, growth effects, developmental effects,behavioral, psychological, attention deficit hyperac-tivity disorder (ADHD), treatment, and outcome. A total of 1417 abstracts were initially assessed forpossible inclusion. After removal of duplicate data,292 were retained for final review based on relevancy and the highest level of available evidence for the

outlined clinical questions. Evidence tables weregenerated for these studies and used by the work group in developing recommendations. The Academy’s previously published guidelines on AD were also evaluated, as were other current publishedguidelines on AD.2-5

The available evidence was evaluated using a uni-fied system called the Strength of RecommendationTaxonomy (SORT) developed by editors of US family medicine and primary care journals (ie, American Family Physician, Fami l y Medicine , Journal of Family Practice , and BMJ USA).6 Evidence was graded using a

3-point scale based on the quality of study methodol-ogy (eg, randomized control trial, case control,prospective/retrospective cohort, case series, etc) andthe overall focus of the study (ie, diagnosis, treatment/prevention/screening, or prognosis) as follows:

I. Good-quality patient-oriented evidence (ie, evi-dence measuring outcomes that matter topatients: morbidity, mortality, symptom improve-ment, cost reduction, and quality of life).

II. Limited-quality patient-oriented evidence.III. Other evidence, including consensus guidelines,

opinion, case studies, or disease-oriented evidence(ie, evidence measuring intermediate, physiologic,

J A M A CAD DERMATOL V OLUME 70, NUMBER 2

Eichenfield et al 339


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or surrogate end points that may or may not reflectimprovements in patient outcomes).

Clinical recommendations were developed basedon the best available evidence. These are ranked asfollows: A. Recommendation based on consistent and

good-quality patient-oriented evidence.B. Recommendation based on inconsistent or

limited-quality patient-oriented evidence.C. Recommendation based on consensus, opinion,

case studies, or disease-oriented evidence.

In situations where documented evidence-baseddata are not available, we have used expert opinion

to generate our clinical recommendations.This guideline has been developed in accordance

with the American Academy of Dermatology (AAD)/ AAD Association Administrative Regulations for Evidence-based Clinical Practice Guidelines (versionapproved May 2010), which includes the opportunity for review and comment by the entire AAD member-ship and final review and approval by the AAD Boardof Directors.7 This guideline will be consideredcurrent for a period of 5 years from the date of publication, unless reaffirmed, updated, or retired ator before that time.

DEFINITION AD is a chronic, pruritic inflammatory skin disease

that occurs most frequently in children, but alsoaffects many adults. It follows a relapsing course. ADis often associated with elevated serum immuno-globulin (IgE) levels and a personal or family history of type I allergies, allergic rhinitis, and asthma. Atopic eczema is synonymous with AD.

INTRODUCTION AD onset is most common between 3 and 6

months of age, with approximately 60% of patients

developing the eruption in the first year of life and90% by 5 years of age.8,9 While the majority of affected individuals have resolution of disease by adulthood, 10% to 30% do not, and a smallerpercentage first develop symptoms as adults.10 ADhas a complex pathogenesis involving genetic,immunologic, and environmental factors that leadto a dysfunctional skin barrier and dysregulation of the immune system. Notable clinical findings includeerythema, edema, xerosis, erosions/excoriations,oozing and crusting, and lichenification, but these vary by patient age and chronicity of lesions. Pruritusis a hallmark of the condition that is responsible formuch of the disease burden borne by patients andtheir families.

DIAGNOSISThe diagnosis of AD is made clinically and is

based on historical features, morphology anddistribution of skin lesions, and associated clinicalsigns. Formal sets of criteria have been developed by various groups to aid in classification.

One of the earliest and most recognized sets of diagnostic criteria is the 1980 Hanifin and Rajkacriteria,11 which requires that 3 of 4 major criteria and3 of 23 minor criteria be met. While comprehensiveand often used in clinical trials, such a large numberof criteria are unwieldy for use in clinical practice.Some of the minor criteria have been noted to bepoorly defined or nonspecific, such as pityriasis alba,

while others, such as upper lip cheilitis andnipple eczema, are quite specific for AD butuncommon.11,12 Several international groups haveproposed modifications to address these limitations(eg, Kang and Tian criteria, International Study of Asthma and Allergies in Childhood [ISAAC]criteria).13-16 The United Kingdom (UK) WorkingParty, in particular, systematically distilled theHanifin and Rajka criteria down to a core set that issuitable for epidemiologic/population-based studiesand that can be used by nondermatologists. Theseconsist of 1 mandatory and 5 major criteria and do

not require any laboratory testing. Both the Hanifinand Rajka and UK Working Party diagnostic schemeshave been validated in studies and tested in severaldifferent populations.12,13,15,17-23

A 2003 consensus conference spearheaded by the American Academy of Dermatology suggestedrevised Hanifin and Rajka criteria that are morestreamlined and additionally applicable to the fullrange of ages affected.24 While this set has not beenassessed in validation studies, it is felt by the current work group that an adaptation of this pragmaticapproach for diagnosing AD in infants, children,

and adults is well suited for use in the clinical setting

Table I. Clinical questions used to structure theevidence review for the diagnosis and assessmentof atopic dermatitis

d What are the most valid and reliable methods for

diagnosing atopic dermatitis?*

d What are the most useful tools to assess the severityand course of atopic dermatitis?*

d What are the patient- and disease-specific outcome

measures used to determine the relative effectiveness

of a given treatment for atopic dermatitis?*d What common clinical associations may affect patients

with atopic dermatitis?*d What are the epidemiologic risk factors associated with

atopic dermatitis?*

*Indicates new clinical questions.

J A M A CAD DERMATOLFEBRUARY 2014

340 Eichenfield et al

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(Box 1). The original UK criteria cannot be applied to very young children, although re visions to includeinfants have since been proposed.25-27

The recommendation for the diagnosis of AD isshown in Table II, and the strength of the recommen-dation is displayed in Table III. AD should be differ-entiated from other red, scaly skin conditions. It isoften difficult to separate AD from seborrheic derma-titis in infancy, andthe 2 conditions may overlap in this

age group. AD usually spares the groin and axillary

regions,while seborrheic dermatitis affectsthese areasand tends not to be pruritic. Particularly if notresponding to therapy, the diagnosis of AD shouldbe re-reviewed and other disorders considered, in-cluding more serious nutritional, metabolic, and im-munologic conditions in children and cutaneous T-cell lymphoma in adults. Allergic contact dermatitismay be both an alternative diagnosis to AD and/or anexacerbator of AD in some individuals (further dis-

cussed in section 4 of the guideline series).

Box 1. Features to be considered in the diagnosis of patients with atopic dermatitis

ESSENTIAL FEATURES—Must be present:d Pruritusd Eczema (acute, subacute, chronic)

, Typical morphology and age-specific patterns*

, Chronic or relapsing history

*Patterns include:

1. Facial, neck, and extensor involvement in infants and children2. Current or previous flexural lesions in any age group3. Sparing of the groin and axillary regions

IMPORTANT FEATURES—Seen in most cases, adding support to the diagnosis:d Early age of onsetd Atopy

, Personal and/or family history

, Immunoglobulin E reactivityd Xerosis

ASSOCIATED FEATURES—These clinical associations help to suggest the diagnosis of atopic dermatitis but

are too nonspecific to be used for defining or detecting atopic dermatitis for research and epidemiologic

studies:d Atypical vascular responses (eg, facial pallor, white dermographism, delayed blanch response)d Keratosis pilaris/pityriasis alba/hyperlinear palms/ichthyosisd Ocular/periorbital changesd Other regional findings (eg, perioral changes/periauricular lesions)d Perifollicular accentuation/lichenification/prurigo lesions

EXCLUSIONARY CONDITIONS—It should be noted that a diagnosis of atopic dermatitis depends on

excluding conditions, such as:d Scabiesd Seborrheic dermatitisd Contact dermatitis (irritant or allergic)d Ichthyosesd Cutaneous T-cell lymphomad Psoriasisd Photosensitivity dermatosesd Immune deficiency diseasesd Erythroderma of other causes

Adapted from Eichenfield et al.24 Used with permission of the American Academy of Dermatology.




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BIOMARKERSThe diagnosis of AD remains clinical, because

there is currently no reliable biomarker that candistinguish the disease from other entities. The mostcommonly associated laboratory feature, an elevatedtotal and/or allergen-specific serum IgE level, is notpresent in about 20% of affected individuals.28 Some

denote ‘‘extrinsic’’ and ‘‘intrinsic’’ groups of diseasebased on the presence or absence of IgE elevation,but whether these are true variants remains contro- versial. Some individuals will later develop elevatedIgE levels, and recent knowledge of skin barrierdefects and studies on epicutaneous sensitizationsuggest that elevated IgE may be a secondary phenomenon.28 Elevated allergen-specific IgE levelsare also nonspecific, because the y are found in 55%of the US general population.29 Although the totalIgE level does tend to vary with disease severity, it isnot a reliable indicator, because some individuals

with severe disease have normal values, and IgE may also be elevated in multiple nonatopic conditions(eg, parasitic infection and certain cancers andautoimmune diseases).28,30,31 Increases in tissuemast cells and peripheral eosinophil counts havealso been evaluated, but with similar inconsistentassociation.30,32-34

Discovery of new T-lymphocyte subsets andnovel cytokines and chemokines have generated amyriad of additional potential biomarkers. Theseinclude serum levels of CD30, macrophage-derivedchemoattractant (MDC), interleukins (IL)-12, -16,

-18, and -31, and thymus and activation-regulatedchemokine (TARC). Some have shown a correlation with AD disease severity using the SCORing AtopicDermatitis (SCORAD) index and other severity scales.35-40 But to date, none have shown reliablesensitivity or specificity for AD to support generalclinical use for diagnosis or monitoring. Most studiessuffer from a small cohort size and involve selectionfrom tertiary care centers with more severe diseaserather than from general populations. Few havecompared levels in AD with that in other eczematousconditions or other atopic conditions to assess

whether the biomarker is a specific indicator for AD.

Markers for prognosis are also inconsistent,although high total serum IgE levels and filaggrin( FLG ) gene null mutations do tend to predict amore severe and protracted course of disease(discussed further belo w in ‘‘Risk factors for diseasedevelopment’’).9,28,41,42 Recommendations for theuse of biomarkers in the assessment of AD areshown in Table IV , and the strength of the recom-mendations are summarized in Table III.

DISEASE SEVERITY AND CLINICAL OUTCOMES ASSESSMENTDisease severity scales

For the measurement of disease severity,28 different scales were identified, without a singlegold standard emerging.43-56 They use variousmethods that include grid patterns and objective

disease features and extent, and some scalesincorporate subjective disease features. The mostcommonly used disease severity scales are theSCORAD index, the Eczema Area and Severity Index (EASI), Investigator’s Global Assessment(IGA), and the Six Area, Six Sign Atopic Dermatitis(SASSAD) severity score.43 These scales are primarily used in clinical trials and rarely in clinical practice, asthey were generally not designed for this purpose.

Scale development in many cases includedrigorous testing and evaluation of the follow-ing statistical properties: inter- and intrarater

reliability, validity (ie, construct, content, andconcurrent), internal consistency reliability, respon-siveness to change, and minimal clinically importantdifference.44,45 The available literature suggests thatthe SCORAD index, the EASI score, and the Patient-Oriented Eczema Measure (POEM) severity scalehave been adequately tested and validated;therefore, their use can be considered whenpractical.44 Of note, the EASI uses objectivephysician estimates of disease extent and severity, while SCORAD incorporates both objectivephysician estimates of extent and severity and sub-

jective patient assessment of itch and sleep loss.50

POEM was specifically designed to measure severity from the patient perspective and uses 7 questionsregarding symptoms and their frequency.43 TheThree Item Severity Scale (TISS) is another simplifiedscale that shows promise for future use in clinicalpractice, but it needs additional testing.44,54

Recognizing the lack of uniformity in disease-severity scale use, international efforts are underway to standardize measured outcomes.57 This includesdevelopment of a core set of valid measures of signs and symptoms that can be feasibly recorded

in controlled trials, which is directed toward

Table II. Recommendation for the diagnosis of atopic dermatitis

Patients with presumed atopic dermatitis should have

their diagnosis based on the criteria summarized in

Box 1. On occasion, skin biopsy specimens or other tests

(such as serum immunoglobulin E, potassium hydroxidepreparation, patch testing, and/or genetic testing) may

be helpful to rule out other or associated skin

conditions.




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improving comparisons across trials and facilitatingmetaanalyses.

Quality of life scales and disease impact measurements

Twenty-two different AD-specific, dermatology-

specific, and generic scales were identified thatmeasure quality of life and other psychologicaloutcomes in patients with AD.43,58-66 These scaleshave been used to assess the impact of AD and theeffects of interventions, as well as to make compar-isons with the impact of other disorders. Carefulconsideration of the scale properties shouldoccur before use, including validity (ie, content,construct, concurrent, and discriminative), reliability (ie, testeretest and internal consistency), respon-siveness to change, and minimal clinically importantdifference.58,60,67,68 In clinical trials, the most com-

monly used scale is the Children’s Dermatology LifeQuality Index (CDLQI), followed by the DermatitisFamily Impact (DFI), the Dermatology Life Quality Index (DLQI), and the Infant’s Dermatology LifeQuality Index,43 but these scales were not generally designed for use in routine clinical practice.69

Additional development and evaluation of practical clinical quality of life scales are needed.This could be done by modifying existing scales intoshort clinical versions or by testing existing scales in aclinic population. Of note, the inclusion of patientassessment of pruritus is critical gi ven its central

contribution to the morbidity of AD.

70,71

Ratings of

itch intensity, whether made by parents for youngchildren or by older individuals for themselves,significantly and inversely correlate with quality of life.72,73 The difficulties associated with itching and

the resultant scratching are typically the first to bementioned by parents when asked about theeffects of their child’s disease.74 The mechanismsunderlying AD-associated itch remain unclear, andare an area of much active research. Sleepdisturbance, the impedance of daily activities(including effects on work or school performance),and persistence of disease are other key measures of disease impact, and represent a patient’s status andoverall well-being.69,75,76 Recommendations onassessment are summarized in Table V and thestrength of recommendations in Table III.

CLINICAL ASSOCIATIONSCommon associations/comorbidities of AD that

have been supported by studies include other atopicconditions, namely food allergies, asthma, andallergic rhinitis/rhinoconjunctivitis.77-84 Some con-sider AD to be the start of the ‘‘atopic march, ’’ giventhe frequent subsequent development of one ormore of the other atopic conditions. However, theassociation of other atopic conditions with AD iscomplex and multifactorial, because this progressiondoes not happen in all individuals. Patients living in

humid climates or developing countries may mani-fest AD only after changing their locale and/or afterthe onset of respiratory allergies.85-88

Sleep disturbance is also common and stems inlarge part from the significant itch associated with AD.69,70,89,90 Sleep is disrupted in up to 60% of children with eczema, increasing to 83% duringexacerbation.91 Along with the affected individual,other family members may also suffer as a result of being awakened.68 Even when in clinical remission,individuals with eczema have more sleepdisturbance than do healthy individuals.91 Greater

skin disease severity also appears to have an effect

Table III. Strength of recommendations for the diagnosis and assessment of atopic dermatitis

Recommendation

Strength of

recommendation

Level

of evidence References

Diagnosis made using criteria in Box 1 C III 12,13,15-23,146-149

No specific biomarkers for diagnosis or severity assessment B II 30-40,150-164

Immunoglobulin E levels not routinely recommended A I

5,30,31,34,35,165,166

Available disease severity scales not for routine clinical use C II 44,45,48,49,54,66,67,167-176

Available quality of life severity scales not for routine clinical use C II 58,60,67,68

Should query itch, sleep, impact on daily activity, and

disease persistence

C III 69-76

Awareness and discussion of common associations C I and II 69,70,77-84,92-98,103,104

Integrated, multidisciplinary approach to care C III 107,108

Table IV. Recommendations for the use of biomarkers in the assessment of atopic dermatitis

For patients with presumed atopic dermatitis, there are no

specific biomarkers that can be recommended for

diagnosis and/or assessment of disease severity.

Monitoring of immunoglobulin E levels is notrecommended

for the routine assessment of disease severity.




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on mood. Depression has been noted in both teensand adults affected with AD.92,93 More recently, therehas been a suggested association of AD with

behavior disorders, including ADHD, especially inchildren.94,95 However, an association does notestablish causality, and the precise nature of therelationship requires additional study, including therole of sleep disturbance and ADHD-like behaviorsand the possibility of nonspecific linkage to any chronic disease of childhood.94

Cancer and obesity have been inconsistently associated with AD. There does not appear to be anincreased risk of skin cancer or of internal malignan-cies, although some data are suggestive of higherrates of lymphoma and lower rates of glioma.96-100 At

present, there are insufficient data to warrant specialscreening or caution. AD has beenlinkedtoobesityina few epidemiologic studies.101,102 However, shortstatureand poor growth have also been documented,particularly in children who suffer from severe skindisease.103-106

The recommendations regarding the assessmentfor clinical associations of AD (Table VI) arebased on group consensus, because there is nohigh-quality, conclusive evidence to show thatscreening for them leads to improved patientoutcomes. The benefits of taking an integrated,

multidisciplinary clinical approach to the care of AD patients with common associations are mainly limited to a few case reports.107,108 Eczema schoolsand other educational programs will be discussed insection 4 of the guidelines.

RISK FACTORS FOR DISEASEDEVELOPMENT

Two risk factors appear to be consistently and strongly associated with the development of AD: (1) a family history of atopy and (2) the loss of

function mutations in the FLG gene.

Approximately 70% of AD patients have a positivefamily history of atopic diseases.109 The odds of developing AD are 2- to 3-fold higher in children with 1 atopic parent, and this increases to 3- to 5-fold

if both parents are atopic.110,111 A maternal history of AD is possibly more predictive.112 The FLG geneencodes profilaggrin, which is degraded to filaggrinmonomers, and these proteins play key roles in theterminal differentiation of the epidermis andformation of the skin barrier, including the stratumcorneum. Filaggrin breakdown products are part of natural moisturizing factor, which contributes toepidermal hydration and barrier function. FLG nullmutations confer a risk for earlier-onset AD, and formore severe, persistent disease.113,114 They also leadto an increased tendency for eczema herpeticum.

Different defects in FLG have been noted in differentethnic populations with AD, showing its importanceto pathogenesis. However, a significant number of patients with AD have no known FLG mutations, andconversely, approximately 40% of individuals with FLG null alleles do not develop AD.113

The type of delivery during childbirth (ie, caesar-ean or vaginal) does not appear to alter AD risk.115

Elevated birth weights may be a risk factor fordisease development, but the effect size is likely small because studies have been conflicting, withsome showing a negative association.116-118

While patients with AD are often sensitized tocertain foods, the timing of solid food introduction or withholding of allergenic foods does not appear toalter the risk for AD.119 Most studies of dietary modification of the maternal or infant diet do notshow a protective effect, although recently pub-lished studies of hydrolyzed formula and probioticsupplementation suggest that these approachescould have a beneficial effect in preventing diseasedevelopment in some high-risk infants who are notexclusively breast fed.120-125 At present, however,there is insufficient evidence to recommend any

specific dietary or other measures as being effective

Table VI. Recommendations for the assessment of clinical associations of atopic dermatitis

Physicians should be aware of and assess for conditions

associated with atopic dermatitis, such as rhinitis/

rhinoconjunctivitis, asthma, food allergy, sleep

disturbance, depression, and other neuropsychiatricconditions, and it is recommended that physicians

discuss them with the patient as part of the treatment/

management plan, when appropriate.

An integrated, multidisciplinary approach to care may be

valuable and is suggested for atopic dermatitis patients

who present with common associations.

Table V. Recommendations for disease severity andclinical outcomes assessment

For the general management of patients with atopic

dermatitis, available disease severity measurement scales

are not recommended for routine clinical practice,

because they were not usually designed for this purpose.

For the general management of patients with atopic

dermatitis, available patient quality of life measurement

scales are not recommended for routine clinical practice.

It is recommended that clinicians ask general questions

about itch, sleep, impact on daily activity, and

persistence of disease, and currently available scales be

used mainly when practical.




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for the primary prevention of AD. Breastfeeding forthe first 6 months of life is encouraged for its otherbenefits for the infant and mother (eg, bonding andpassive immunity).

There are no consistent findings to suggest thatmale or female sex affects AD risk, but being of blackrace does appear to increase risk.126 A higher level of parental education is a risk factor for disease, but theeffect of socioeconomic status is unclear.126,127

Previous studies found a higher risk of AD in highersocioeconomic groups, but more recent studies failedto confirm these findings.128,129 Living in urban areasappears likely to increase the risk of AD,but studies attempting to identify causati ve environ-mental agents have not been conclusive.130 Daycaremay influencethe risk of AD development, but studiesthat offer better control for confounders are neededbefore additional conclusions can be made.126,131

The effect of exposure to pets is unclear, withconflicting data.132-134 Two recent studies haveshown that cat but not dog ownership enhancedthe effect of filaggrin mutations in promoting thedevelopment of AD.135,136 While patients with ADare often sensitized to house dust mites, there is notstrong evidence to show that dust mite avoidancestrategies prevent AD.137,138 The most recentsystematic review regarding early life microbialexposures found evidence that exposures to endo-toxin, farm animals, and dogs may protect against AD.139 The consumption of unpasteurized milk and

acquired helminth infections may also be protective,but are not recommended measures because of theirpotential associated health risks.

No definitive conclusions can be drawn regardingearly antibiotic exposure and the risk of AD.85,140,141

Although studies are inconsistent, personal andsecond hand/household smoking status do not ap-pear to significantly affect AD development142-145;however, smoking is detrimental to those withasthma and has many other negative health risks.

GAPS IN RESEARCH

In review of the currently available highest level of evidence, the expert work group acknowledges that while much is known about the diagnosis and evalu-ation of AD, much has yet to be learned. Significantgaps in research were identified, including but notlimited to: validation studies of the AAD workgroupdiagnostic criteria, development, validation, and uni-formity in use of disease severity and quality of lifemeasurements applicable to a busy clinical practiceenvironment, interventional studies testing impact of multidisciplinary management on AD outcomes, andadditional quality, controlled studies on epidemio-

logic risk factors for disease. It is hoped that additional

knowledge of AD pathogenesis will soon lead to aproven biomarker for diagnosis and/or monitoring,and thatAD-associatedpruritusis betterunderstood togenerate improved therapeutic options.

We thank Melinda Jen, MD, Michael Osofsky, MD,

Kathleen Muldowney, MLS, Charniel McDaniels, MS,and Tammi Matillano for technical assistance in thedevelopment of this manuscript. We also thank the AADBoard of Directors, the Council on Science and Research,the Clinical Guidelines Committee, and all commenting

Academy members for their thoughtful and excellentcomments.

Dr Tom is supported by a National Institutes of Health/National Institute of Arthritis and Musculoskeletaland Skin Diseases research career development grant(K23AR060274). The content is solely the responsibility of the authors and does not necessarily represent theofficial views of the National Institute of Arthritis and

Musculoskeletal and Skin Diseases or the NationalInstitutes of Health.

The American Academy of Dermatology (AAD) strivesto produce clinical guidelines that reflect the best availableevidence supplemented with the judgment of expertclinicians. Significant efforts are taken to minimize thepotential for conflicts of interest to influence guidelinecontent. Funding of guideline production by medical orpharmaceutical entities is prohibited, full disclosure isobtained and evaluated for all guideline contributors,and recusal is used to manage identified relationships.The AAD conflict of interest policy summary may be

viewed at www.aad.org.

The information below represents the authors’identified relationships with industry that are relevant tothe guideline. Relevant relationships requiring recusal fordrafting of guideline recommendations and content werenot noted for this section.

Lawrence F. Eichenfield, MD: Dr Eichenfield served as aconsultant for Anacor, Bayer, and Leo Pharma receivinghonoraria and TopMD receiving stock options; was aconsultant and speaker for Galderma, receiving honoraria;served as a consultant, speaker, and member of theadvisory board for Medicis/Valeant, receiving honoraria;and was an investigator for Anacor, Astellas, Galderma,and Leo Pharma, receiving no compensation.

SarahL. Chamlin, MD: Dr Chamlin served on theadvisory boards for Galderma and Valeant, receiving honoraria.

Steven R. Feldman, MD, PhD: Dr Feldman served on theadvisory boards for Amgen, Doak, Galderma, Pfizer,Pharmaderm, Skin Medica, and Stiefel, receivinghonoraria; was a consultant for Abbott, Astellas,Caremark, Coria, Gerson Lehrman, Kikaku, Leo Pharma,Medicis, Merck, Merz, Novan, Peplin, and Pfizer receivinghonoraria and Celgene, HanAll, and Novartis receivingother financial benefits; was a speaker for Abbott, Amgen,

Astellas, Centocor, Dermatology Foundation, Galderma,Leo Pharma, Novartis, Pharmaderm, Sanofi-Aventis,Stiefel, and Taro, receiving honoraria; served as astockholder and founder for Causa Technologies and



http://www.aad.org/http://www.aad.org/


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Medical Quality Enhancement Corporation, receivingstock; served as an investigator for Abbott, Amgen,

Anacor, Astellas, Basilea, Celgene, Centocor, Galderma,Medicis, Skin Medica, and Steifel, receiving grants, andSuncare Research, receiving honoraria; and had otherrelationships with Informa, UptoDate, and Xlibris

receiving royalty and Medscape receiving honoraria. Jon M. Hanifin, MD: Dr Hanifin served on the advisory

board for Chugai Pharma USA receiving honoraria; was aconsultant for GlaxoSmithKline, Merck Elocon Advisory Board, Pfizer, and Valeant Elidel Advisory Board receivinghonoraria; and served as an investigator for Asubio andMerck Sharp & Dohme receiving grants.

Eric L. Simpson, MD: Dr Simpson served as aconsultant for Asubio, Brickell Biotech, Galderma,Medicis, Panmira Pharmaceuticals, and Regeneron, and aspeaker for Centocor and Galderma receiving honoraria;and was an investigator for Amgen, Celgene, Galderma,and Regeneron receiving other financial benefits.

James N. Bergman, MD: Dr Bergman served as a speakerand consultant for Pediapharm receiving honoraria.

David E. Cohen, MD: Dr Cohen served on the advisory boards and as a consultant for Onset, Ferndale Labs, andGalderma, receiving honoraria; served on the board of directors and as a consultant for Brickell Biotechnology and Topica receiving honoraria, stock, and stock options;and was a consultant for Dermira and Dr Tatoff receivinghonoraria and stock options.

Alfons Krol, MD: Dr Krol served as an investigator forPierre-Fabre receiving grants.

Amy S. Paller, MD: Dr Paller served as a consultant to AbbVie, Alwyn, Amgen, Galderma, GlaxoSmithKline, Leo

Pharma, Lundbeck, Medicis, Pfizer, Promius, Sanofi/Regeneron, and TopMD receiving honoraria; and was aninvestigator for Amgen, Galderma, and Leo Pharmareceiving no compensation.

Robert A. Silverman, MD: Dr Silverman served as aspeaker for Galderma and Promius receiving honoraria.

Craig A. Elmets, MD: Dr Elmets served on a data safety monitoring board for Astellas receiving honoraria.

Robert Sidbury, MD, Wynnis L. Tom, MD, Timothy M.Berger, MD, Kevin D. Cooper, MD, Kelly M. Cordoro, MD,Dawn M. Davis, MD, David J. Margolis, MD, PhD, KathrynSchwarzenberger, MD, Hywel C. Williams, PhD, JulieBlock, Christopher G. Harrod, MS, and Wendy Smith

Begolka, MBS, have no relevant relationships to disclose.

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